Nitric oxide donor compositions, methods, apparatus, and kits for preventing or alleviating vasoconstriction or vasospasm in a mammal

Abstract

The invention relates to compositions, methods, apparatus, and kits for alleviating or preventing vasoconstriction or vasospasm in a mammal. The compositions, methods, apparatus, and kits are also useful for alleviating or preventing ischemic tissue damage resulting from ischemia associated with cerebral vasoconstriction which follows aneurysmal subarachnoid hemorrhage, with embolic stroke, with coronary artery obstruction, and with other conditions. These compositions, methods, apparatus, and kits generally relate to adventitial (i.e. extra-luminal) administration of a nitric oxide donor compound to a blood vessel in a mammal.

What is claimed is:  
     
       1. A method of alleviating cerebral vasoconstriction in a human having a constricted cerebral blood vessel, the method comprising intrathecally administering a nitric oxide donor compound to the human in an amount effective to alleviate constriction of the vessel. 
     
     
       2. The method of  claim 1 , wherein the vessel is selected from the group consisting of the right anterior cerebral artery, the right middle cerebral artery, the right posterior communicating artery, the left anterior cerebral artery, the left middle cerebral artery, and the left posterior communicating artery. 
     
     
       3. The method of  claim 1 , wherein the compound is administered by delivering the compound to the cerebrospinal fluid of the human. 
     
     
       4. The method of  claim 3 , wherein the cerebrospinal fluid is withdrawn from the subaraclnoid space of the human, combined with the compound, and returned to the subarachnoid space. 
     
     
       5. The method of  claim 3 , wherein the cerebrospinal fluid is withdrawn from the subarachnoid space of the human, combined with a pharmaceutical composition comprising the compound, and returned to the subarachnoid space. 
     
     
       6. The method of  claim 1 , wherein the compound is administered in a sustained-release formulation. 
     
     
       7. The method of  claim 1 , wherein the compound is a nitroprusside salt, and wherein from about 38 to 336 micromoles per day of the compound are administered to the human. 
     
     
       8. The method of  claim 7 , wherein from about 38 to 115 micromoles per day of the compound is administered to the human. 
     
     
       9. The method of  claim 1 , wherein the compound is selected from the group consisting of nitroglycerine, arginine, and a nitroprusside salt. 
     
     
       10. The method of  claim 9 , wherein the compound is sodium nitroprusside. 
     
     
       11. The method of  claim 10 , wherein the compound is administered in the form of a pharmaceutical composition comprising the compound and a scavenger compound selected from the group consisting of a cyanide scavenger, and a cyanate scavenger. 
     
     
       12. The method of  claim 1 , wherein the amount of the compound administered is insufficient to induce either of systemic hypotension and cerebral hypertension in the human. 
     
     
       13. The method of  claim 1 , further comprising administering a compound selected from the group consisting of an anti-inflammatory agent, an antibiotic, an oxyhemoglobin-reducing compound, a thrombolytic agent, and an anti-emetic compound to the human. 
     
     
       14. The method of  claim 1 , wherein the compound decomposes under physiological conditions. 
     
     
       15. The method of  claim 1 , wherein the compound is not a substrate of NO synthase. 
     
     
       16. The method of  claim 1 , wherein the compound has a short half-life in solution and is administered within minutes after solvating the compound. 
     
     
       17. The method of  claim 16 , wherein the compound is solvated by mixing the compound with cerebrospinal fluid obtained from the human. 
     
     
       18. The method of  claim 17 , wherein the cerebrospinal fluid is withdrawn from the human, mixed with the compound, and then returned to the subarachnoid space of the human. 
     
     
       19. The method of  claim 1 , wherein the human is experiencing chronic delayed cerebral vasoconstriction. 
     
     
       20. The method of  claim 1 , wherein the human has experienced a subarachnoid hemorrhage. 
     
     
       21. The method of  claim 1 , wherein the human has experienced an aneurysmal subarachnoid hemorrhage. 
     
     
       22. The method of  claim 1 , wherein the human is experiencing an early embolic stroke. 
     
     
       23. The method of  claim 1 , wherein the human has experienced a stroke. 
     
     
       24. A method of preventing cerebral vasoconstriction in a human during the period during which a nitric oxide donor compound persists in the human following intrathecal administration, the method comprising intrathecally administering the compound to the human during the period in an amount effective to prevent constriction of a cerebral blood vessel during that period. 
     
     
       25. The method of  claim 24 , wherein the compound is sodium nitroprusside. 
     
     
       26. The method of  claim 25 , wherein the amount of sodium nitroprusside administered in a one-day period is not more than 24 milligrams. 
     
     
       27. The method of  claim 26 , wherein the amount is in the range from 4 to 24 milligrams. 
     
     
       28. The method of  claim 24 , wherein the compound is administered in the form of a sustained-release formulation. 
     
     
       29. The method of  claim 24 , wherein the compound is a nitroprusside salt, and wherein from about 15 to 92 micromoles per day of the compound are administered to the human. 
     
     
       30. A method of dilating a constricted or spastic cerebral blood vessel in a human, the method comprising intrathecally administering a nitric oxide donor compound to the vessel in an amount effective to dilate the vessel. 
     
     
       31. The method of  claim 30 , wherein the compound is a nitroprusside salt, and wherein from about 38 to 336 micromoles per day of the compound are administered to the human. 
     
     
       32. A method of alleviating ischemia in a cerebral tissue of a human, the method comprising intrathecally administering a nitric oxide donor compound to the tissue in an amount effective to alleviate ischemia in the tissue. 
     
     
       33. The method of  claim 32 , wherein the compound is a nitroprusside salt, and wherein from about 38 to 336 micromoles per day of the compound are administered to the human. 
     
     
       34. A method of preventing ischemia in a cerebral tissue of a human during the period during which a nitric oxide donor compound persists in the human following intrathecal administration, the method comprising intrathecally administering the compound to the tissue in an amount sufficient to prevent ischemia in the tissue during that period. 
     
     
       35. The method of  claim 34 , wherein the compound is a nitroprusside salt, and wherein from about 15 to 92 micromoles per day of the compound are administered to the human. 
     
     
       36. A method of alleviating cerebral vasoconstriction in a human having a constricted cerebral blood vessel, the method comprising intrathecally administering a nitric oxide donor compound which decomposes under physiological conditions to the human in an amount effective to alleviate constriction of the vessel. 
     
     
       37. The method of  claim 36 , wherein the compound is a nitroprusside salt, and wherein from about 38 to 336 micromoles per day of the compound are administered to the human.